Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extranodal natural killer (NK)/T-cell lymphoma, nasal type, and aggressive NK-cell leukemia are rare, and their standard therapy has not been established. They are Epstein-Barr virus-associated lymphoid malignancies, and tumor cells express P-glycoprotein leading to multidrug resistance of the disease. Patients with stage IV, relapsed or refractory diseases have a dismal prognosis, with survival measured in months only. To develop an efficacious chemotherapeutic regimen, we conducted a dose-escalation feasibility study of a new chemotherapeutic regimen, SMILE, comprising the steroid dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide. The components of SMILE are multidrug resistance-unrelated agents and etoposide. Etoposide shows both in vitro and in vivo efficacy for Epstein-Barr virus-associated lymphoproliferative disorders. Eligible patients had newly diagnosed stage IV, relapsed or refractory diseases after first-line chemotherapy, were 15-69 years of age, and had satisfactory performance scores (0-2). Four dose levels of methotrexate and etoposide were originally planned to be evaluated. At level 1, six patients with extranodal NK/T-cell lymphoma, nasal type, were enrolled. Their disease status was newly diagnosed stage IV (n = 3), first relapse (n = 2), and primary refractory (n = 1). All of the first three patients developed dose-limiting toxicities, and one of them died of sepsis with grade 4 neutropenia. A protocol revision stipulating early granulocyte colony-stimulating factor administration was made. Two out of three additional patients developed dose-limiting toxicities that were all manageable and transient. For the six enrolled patients, the overall response rate was 67% and the complete response rate was 50%. Although its safety and efficacy require further evaluation, we recommend a SMILE chemotherapy dose level of 1 for further clinical studies.
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PMID:Phase I study of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy for advanced-stage, relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma and leukemia. 1829 94

Extranodal NK/T cell lymphoma, nasal type (ENKL) with advanced stage and aggressive NK-cell leukemia (ANKL) are highly aggressive neoplasms with a dismal clinical outcome. It is well known that P-glycoprotein, which is a product of MDR1 gene and related to multi-drug resistance, is expressed on tumor cells of ENKL or ANKL. This is a major reason for the refractoriness to conventional chemotherapeutic regimens for malignant lymphoma containing anthracycline. However, recent studies have identified that several drugs including L: -asparaginase, methotrexate and alkylators show excellent effect for these tumors. The SMILE (steroid, methotrexate, ifosfamide, L: -asparaginase and etoposide) regimen is one of the promising regimens for advanced or relapsed/refractory ENKL, but its myelotoxicity is strong. ANKL needs another treatment strategy because of a systemic disease progression and extensive organ insufficiency. Optimal treatment scheme using such effective agents for these unfavorable NK-cell tumors should further be explored.
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PMID:Treatment of advanced extranodal NK/T cell lymphoma, nasal-type and aggressive NK-cell leukemia. 2111 47

The current World Health Organization (WHO) classification includes two types of natural killer (NK)-cell lymphomas: extranodal NK/T-cell lymphoma, nasal type (ENKL), and aggressive NK-cell leukemia (ANKL). These diseases are mostly endemic to East Asia and Latin America. The Epstein-Barr virus (EBV) is usually detected in tumor cells, suggesting that EBV plays an important role in lymphomagenesis. At the site of origin, ENKL can be divided into two major subtypes: nasal and extranasal diseases. The advanced disease presentation, highly aggressive clinical course, and poor prognosis of the latter are analogous to ANKL. It is well known that P-glycoprotein, which is a product of the multi-drug resistance (MDR1) gene, is expressed on neoplastic cells of ENKL or ANKL. This is a major cause of the refractoriness of malignant lymphoma to conventional chemotherapeutic regimens containing anthracycline. Recent studies, however, have identified that L-asparaginase-containing regimens, such as SMILE (steroid, methotrexate, ifosfamide, L-asparaginase and etoposide), are effective for ENKL. Considering the myelotoxicity of SMILE, its use in the treatment of ANKL needs some modifications, but this treatment scheme is promising in improving the prognosis of NK-cell lymphomas.
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PMID:NK/T-cell lymphomas: pathobiology, prognosis and treatment paradigm. 2263 6

Epstein-Barr virus (EBV)-associated natural killer (NK)/T-cell lymphomas show a geographical predilection for Asian and South American populations and are rare in Western countries. They predominantly occur in extranodal sites, including the nasal or paranasal areas, and less frequently in the localized nodal lesion. Most of the tumor cells exhibit a cytotoxic phenotype, characterized primarily by the expression of granzyme B and perforin. EBV is usually detected in tumor cells by using EBV-encoded small RNA in situ hybridization (EBER), suggesting that EBV plays an important role in lymphomagenesis. In this chapter, we have described 2 diseases: 1) extranodal NK/T-cell lymphoma, nasal type (ENKL), representative of extranodal EBV-associated NK/T-cell lymphoma; and 2) nodal cytotoxic molecule-positive EBV-positive peripheral T-cell lymphoma, not specified type (CM + EBV + PTCL-N), representative of nodal lymphoma. Both ENKL and nodal CM + EBV + PTCL-N are intractable to standard chemotherapy. Although ENKL is sensitive to radiotherapy, it shows a poorer response to chemotherapeutic agents than other lymphomas because of P-glycoprotein expression. P-glycoprotein is a product of the multidrug resistance (MDR1) gene, which is a major cause of the refractoriness of malignant lymphomas to conventional chemotherapeutic regimens containing anthracycline. l-asparaginase-containing regimens such as SMILE (steroid, methotrexate, ifosfamide, l-asparaginase, and etoposide) are effective for ENKL. Evaluation of effective chemotherapy for nodal CM + EBV + PTCL-N is ongoing.
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PMID:Epstein-Barr virus-associated natural killer/T-cell lymphomas. 2376 37

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKL) is one of the uncommon subtypes of malignant lymphoma, and predominantly occurs in the nasal or paranasal areas and less frequently in the skin. Previously, its prognosis was poor due to the expression of P-glycoprotein, which actively exports several anticancer agents outside the lymphoma cells. However, in recent years, novel therapeutic approaches such as simultaneous chemoradiotherapy or l-asparaginase-based regimens including SMILE (steroid, methotrexate, ifosfamide, l-asparaginase, and etoposide) improved the response to therapy and survival of ENKL patients. Epstein-Barr virus (EBV) is present in lymphoma cells of almost all patients, accounting for the pathogenesis of ENKL. Fragmented EBV-DNA is released from tumor cells, and can be detected in the peripheral blood of patients. The EBV-DNA copy numbers are associated with tumor burden, and can predict the prognosis of ENKL, as well as the toxicity against chemotherapy. Based on this recent progress, ENKL is currently categorized as a lymphoma with intermediate prognosis, but the overall treatment results are not satisfactory. Further improvement of the prognosis of ENKL is therefore warranted, including the optimal use of hematopoietic stem cell transplantation (HSCT).
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PMID:Pathogenesis and treatment of extranodal natural killer/T-cell lymphoma. 2446 15

P-glycoprotein (Pgp) inhibition has been considered as an effective strategy towards combating multidrug-resistant cancers. Owing to the substrate promiscuity of Pgp, the classification of its interacting ligands is not an easy task and is an ongoing issue of debate. Chemical structures can be represented by the simplified molecular input line entry system (SMILES) in the form of linear string of symbols. In this study, the SMILES notations of 2254 Pgp inhibitors including 1341 active, and 913 inactive compounds were used for the construction of a SMILE-based classification model using CORrelation And Logic (CORAL) software. The model provided an acceptable predictive performance as observed from statistical parameters consisting of accuracy, sensitivity and specificity that afforded values greater than 70% and MCC value greater than 0.6 for training, calibration and validation sets. In addition, the CORAL method highlighted chemical features that may contribute to increased and decreased Pgp inhibitory activities. This study highlights the potential of CORAL software for rapid screening of prospective compounds from a large chemical space and provides information that could aid in the design and development of potential Pgp inhibitors.
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PMID:Large-scale classification of P-glycoprotein inhibitors using SMILES-based descriptors. 2805 66